The objective of our Neurotrauma Research Center at the University of Miami is to carry out a program of integrated multi-disciplinary experimental research into the mechanisms and therapies for traumatic brain injury (TBI). The ultimate goal is to identify factors resulting from TBI which may be amenable to specific therapeutic interventions in the acute, subacute, and chronic stages. This current Program Project consists of investigate proposals directed at developing novel strategies and providing new data concerning recovery of function after TBI. These investigations are supported by Core facilities in the areas of animal physiology, neuropathology, molecular biology, image processing, and neurobehavior. Established animal models,, including fluid-percussion (F-P) injury and cortical impact injury in rats and mice, are utilized. Project 0007 will investigate mechanisms and treatment of slowly progressive white and gray matter damage after TBI. Specifically, the importance of abnormal protein aggregation, chronic hypoperfusion, excitotoxic and apoptotic cell injury will be investigated. The studies proposed in Project 0008 will investigate therapeutic strategies targeting endogenous reparative processes after trauma and the potential of using CNS stem cell transplantation to restore function. This project will first characterize the temporal and regional patterns of cellular proliferation after injury. Treatments will include neurotrophin administration and in vitro strategies to direct cellular differentiation. Multi-potent CNS stem cells whose fate can be potentially controlled will be transplanted into the injured brain to remyelinate axons, promote axonal regeneration, to reconstruct circuitry, and to replace neurons and restore function. Project 0009 will examine molecules that function to regulate axonal guidance and synaptogenesis in the post-injured hippocampus in an attempt to develop new therapeutic strategies to promote recovery. These studies will employ gene targeted knockout mice to examine whether Ephrins and Eph receptors function in the hippocampus, regulate axonal growth and plasticity following TBI.. Finally, Project 0010 will study the ultrastructural, molecular, and functional alterations in synaptic plasticity and determine the importance of these alterations in the behavioral and neuronal consequences of TBI. The Program Project is supported by an established group of scientists who provide the expertise necessary to conduct this multi-disciplinary program in TBI. Together, these experimental studies should enhance our understanding of the critical events associated with acute and more chronic CNS injury and help identify novel treatment strategies to promote neuroprotection, neuron replacement, remyelination, and recovery of function in human CNS injury.